Changes In Sodium Reabsorption Research Articles

Clinic and ambulatory blood pressure in relation to the interaction between plasma advanced glycation end products and sodium dietary intake and renal handling.

Advanced glycation end product (AGE) clearance may cause renal tubular injuries, such as changes in sodium reabsorption. We hypothesize that AGEs interact with sodium metabolism to influence blood pressure (BP). The study participants were outpatients who were suspected of having hypertension but had not been treated with antihypertensive medication. Clinic and ambulatory blood pressures were measured at baseline (n = 989) and during follow-up (median, 4.4 years, n = 293). Plasma AGE concentrations were measured by enzyme-linked immunosorbent assay. Twenty-four-hour urine was collected for measurements of creatinine, sodium and lithium. In a cross-sectional analysis (n = 989), subjects in the top quintile versus quintiles 1-4 of plasma AGE concentration had significantly (P ≤ 0.004) lower fractional excretion of lithium (18.3% vs. 21.6%) and fractional distal reabsorption rate of sodium (95.0% vs. 95.8%) but similar BP (P ≥ 0.25). However, there was an interaction between plasma AGE concentration and urinary sodium excretion in relation to diastolic BP (P ≤ 0.058). Only in participants with low urinary sodium chloride excretion (≤6 grams/day, n = 189), clinic (84.3 vs. 80.2 mmHg), 24-h (83.9 vs. 80.4 mmHg), daytime (87.8 vs. 84.8 mmHg) and nighttime (75.1 vs. 72.1 mmHg) diastolic BP at baseline were higher (P ≤ 0.05) in the top quintile than in quintiles 1-4 of plasma AGE concentration. In the longitudinal study (n = 383), similar trends were observed, with significant (P ≤ 0.05) differences in the increment in daytime diastolic BP (6.8 vs. -1.7 mmHg) and incidence of ambulatory and treated hypertension (hazard ratio 3.73) during follow-up. In conclusion, AGEs were associated with high BP, probably via enhanced proximal sodium handling and on low dietary sodium intake.

Paracrine Communication Links Sodium Chloride Cotransporter Activity in the Distal Convoluted Tubule to Remodeling of the Aldosterone‐Sensitive Distal Nephron

We recently discovered that cell‐specific expression of constitutively active SPAK (CA‐SPAK) in the early distal tubule is sufficient to drive a remodeling process of the entire distal nephron that includes structural dystrophy of the aldosterone‐sensitive distal nephron and inhibition of ROMK and ENaC (Grimm et al, JASN ’17). Here, we tested the hypothesis that SPAK‐activation of NCC stimulates the release of paracrine or autocrine factors that cause the dystrophic response in the CNT.We found increased levels of PGE2 in kidney cortical homogenates of CA‐SPAK mice compared to control mice. Comparable elevation of PGE2 was also observed when NCC was physiologically activated by feeding wild‐type mice (WT) a low potassium diet (LKD). Administration of the NCC‐blocking diuretic, hydrochlorothiazide, to either CA‐SPAK or WT mice on LKD, restored PGE2 to control levels, but had no effect on PGE2 of WT or SPAK KO mice. Thus, PGE2 is elevated in response to super activation of NCC.PGE2 synthesis is mediated by prostaglandin E synthase isoforms. As revealed in western blot analysis, the microsomal prostaglandin E synthase‐1(mPGES1) was elevated in the kidney cortex of CA‐SPAK mice and WT mice on LKD compared to control mice. Quantitative microscopy of mPGES1 surprisingly revealed the augmentation of mPGES1 was confined to the CNT and CCD of CA‐SPAK and LKD treated mice. No changes in mPGES1 were observed in the DCT1.In conclusion, these studies identify PGE2 as a potential remodeling autocrine that is released from the CNT and CCD in response to activation of NCC. We speculate that decreased sodium delivery to the CNT and CCD when NCC is activated drives the response, similar to the mechanism by which PGE2 synthesis is stimulated in the macula densa with changes in sodium reabsorption in upstream tubule segments. The autocrine pathway provides a novel means to communicate potassium sensing in the DCT to potassium secretion in the ASDN.Support or Funding InformationSupported by the NIDDK and Fondation LeducqThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of SGLT Inhibition on Medullary Oxygen Consumption: A Multi‐Nephron Model of the Rat Kidney

The objective of this study was to investigate how changes in sodium reabsorption in the proximal tubule affect oxygen (O2) consumption and the metabolic efficiency of the kidney. To do so, we developed a detailed mathematical model of solute transport in a multi‐nephron representation of the rat kidney. The model represents one superficial nephron and five juxtamedullary nephrons with loops of Henle reaching to differing depths of the inner medulla. The six representative nephrons merge at the entrance of the cortical collecting duct. Glucose is reabsorbed via sodium‐glucose cotransporters (SGLTs) in the proximal tubules, which express SGLT2 in S1–S2 and the SGLT1 in S3. We used the model to investigate the effect of inhibiting SGLT2, a novel treatment for reducing proximal tubule glucose uptake in diabetes, on renal Na+ transport and renal oxygen consumption (QO2). Inhibiting SGLT2 shifts Na+ transport to downstream nephron segments, increasing their QO2. In particular, the S3 segment and medullary thick ascending limb (mTAL) are at risk for hypoxic injury. Dual SGLT1‐SGLT2 inhibition protects the S3 segment, but could further lower mTAL oxygenation. We considered the importance of the GFR‐lowering effect of SGLT2 inhibitors. Additionally, we used the model to determine the optimal combination of SGLT1 and SGLT2 inhibition, in terms of reducing tubular glucose uptake while maintaining sufficiently low S3 and mTAL QO2.Support or Funding InformationThis research was supported in part by NIH grant DK‐89066.

SGLT2 Inhibition Is Predicted to Increase NaCl Delivery to the Medullary Thick Ascending Limb But Not to Significantly Elevate Its Oxygen Consumption

The objective of this study was to investigate how changes in sodium reabsorption in the proximal tubule affect oxygen (O2) consumption and the metabolic efficiency of the nephron. To do so, we developed a detailed mathematical model of solute transport in a short‐loop nephron of the rat kidney. Glucose is reabsorbed via sodium‐glucose cotransporters (SGLTs) in the proximal tubule, which primarily expresses the isoforms SGLT2 in S1‐S2 and SGLT1 in S3. We used the model to investigate the effect of inhibiting SGLT2, a novel treatment for reducing proximal tubule glucose uptake in diabetes, on renal Na+ transport (TNa) and renal oxygen consumption (QO2). Inhibiting SGLT2 shifts Na+ transport to downstream nephron segments, possibly increasing their QO2. Of particular concern are the S3 segment and medullary thick ascending limb (mTAL), which are at risk for hypoxic injury. Dual SGLT2‐SGLT1 inhibition protects the S3 segment, but could further reduce mTAL oxygenation. Model simulations suggest that SGLT2 inhibition substantially increases S3 TNa and QO2. In contrast, mTAL TNa and QO2 is insensitive to SGLT inhibition and the resulting increase in Na+ load, because under physiological conditions luminal [Na+] is sufficiently high that the Na+/K+‐ATPase pump is nearly carrier‐saturated. We also used the model to determine the optimal combination of SGLT1 and SGLT2 inhibition, in terms of suppressing tubular glucose uptake and maintaining a sufficiently low S3 QO2. This research was supported in part by NIH grants DK‐89066 and DK‐56248.

Connexin 37 is localized in renal epithelia and responds to changes in dietary salt intake

Connexins are the main components of gap junction channels, which are important for intercellular communication. In the kidney, several members of the connexin (Cx) family have been identified. Renal vascular expression and hemodynamic impacts have so far been shown for Cx37, Cx40, and Cx43. Additionally, Cx30, Cx30.3, and Cx43 have been identified to be part of tubular epithelial gap junctions and/or hemichannels. However, the localization and role of other Cx family members in renal epithelial structures remain undetermined. We aimed to localize Cx37 in the kidney to obtain information on its epithelial expression and potential functions. Immunohistochemistry in rodent kidney showed characteristic punctate patterns in the vasculature and along the nephron. Strong basolateral expression was found in the thick ascending limb and distal convoluted tubule. Weaker abundances were found in the proximal tubule and the collecting duct also at the basolateral side. In situ hybridization and real-time PCR of isolated nephron segments confirmed this distribution at the mRNA level. Ultrastructurally, Cx37 immunostaining was confined to basolateral cell interdigitations and infoldings. As a functional approach, rats were fed low- or high-salt diets. Compared with control and high-salt diets, rats treated with low-salt diet showed significantly increased Cx37 mRNA and protein levels. This may be indicative of an adaptive tubular response to changes in sodium reabsorption. In summary, renal epithelia express Cx37 in their basolateral membranes. Here, the formation of Cx37 gap junctions may be involved in cellular communication and adjustments of vectorial epithelial transport.

Influence of renal sympathetic nerve stimulation on renal function in the primate.

In anesthetized Macaca fascicularis monkeys renal sympathetic nerves were stimulated electrically while changes in renal function were measured. The range of stimulation frequencies was 0.25-4.0 Hz. In the primate the stimulation threshold for changes in renal vascular resistance at a renal perfusion pressure of 100 mmHg was between 1 and 2 Hz. Vascular resistance increased progressively at higher stimulation frequencies. The threshold for changes in sodium reabsorption was somewhat lower (between 0.5 and 1 Hz). At higher stimulation frequencies sodium excretion was dramatically reduced. Renin secretion was not significantly affected at 0.25 and 0.5 Hz stimulation and rose significantly only at stimulation frequencies of 1.0 Hz or above. Thus renal sympathetic nerves in the primate appear to influence renal vascular resistance and electrolyte excretion in a manner that is quantitatively similar to that seen in other species. However, in the primate it was not possible to stimulate renin secretion in the absence of changes in renal blood flow and sodium reabsorption.

An investigation into the neural regulation of calcium excretion by the rat kidney.

1. An investigation was undertaken to examine the action of the renal nerves on the reabsorption of calcium ions from the left kidney of sodium pentobarbitone anaesthetized rats. 2. Renal denervation had no effect on renal haemodynamics but increased urine flow, calcium excretion, absolute and fractional sodium excretions by 26% (P less than 0.02), 73% (P less than 0.02), 90% (P less than 0.001) and 82% (P less than 0.01), respectively, without affecting the calcium to sodium excretion ratio. In a group of animals which were similarly prepared but the renal nerves were not sectioned, neither renal blood flow, nor the excretion of water, calcium or sodium changed during the time course of the experiment although glomerular filtration rate increased significantly (P less than 0.05) by 19%. 3. Low rates (0.8-1.5 Hz at 15 V, 0.2 ms) of renal nerve stimulation did not change renal haemodynamics but reduced urine flow by 31% (P less than 0.001), calcium excretion by 32% (P less than 0.001), sodium excretion by 32% (P less than 0.001) and fractional sodium excretion by 32% (P less than 0.01) while the calcium to sodium excretion ratio was unaffected. Renal nerve stimulation at 3-5 Hz reduced renal blood flow by 15% (P less than 0.02), did not change glomerular filtration rate and reduced urine flow, calcium excretion, absolute and fractional sodium excretions by 35% (P less than 0.01), 30% (P less than 0.01), 32% (P less than 0.01) and 32% (P less than 0.05), respectively, while the calcium to sodium excretion ratio remained unchanged. 4. These data show that the renal nerves can modulate the excretion of calcium by a mechanism which is independent of renal haemodynamics and which may represent a direct action of the nerves on the calcium reabsorptive processes of the tubular cells. It remains to be determined whether this neural control of calcium reabsorption is a direct one or indirect via changes in sodium reabsorption.

Role of hydrostatic and oncotic pressures in renal sodium reabsorption.

Physical factors, and renal interstitial hydrostatic pressure in particular, have an important effect on sodium excretion by the kidney. Changes in hydrostatic and oncotic pressures in the peritubular microcirculation may have effects on proximal tubule reabsorption under some, but not all, circumstances. In regard to control of sodium excretion, the loop of Henle may be a particularly important segment which is sensitive to transepithelial hydrostatic pressure changes. There is little evidence to support an effect of physical factors on sodium reabsorption by the distal tubule. The collecting tubule may be another pressure-sensitive site; however, changes in sodium reabsorption by deep nephrons in the kidney may account for changes that have been attributed to the collecting duct. Changes in intrarenal pressure may be an important link in the regulation of sodium excretion, particularly in pathological circumstances, such as the exaggerated natriuresis of hypertension and the sodium retention seen in congestive heart failure.

Oxygen requirement of bicarbonate-dependent sodium reabsorption in the dog kidney.

The ratio between changes in sodium reabsorption and renal oxygen consumption (Na/O2) was measured in anesthetized dogs at high plasma bicarbonate concentration (32 +/- 1 mM); ethacrynic acid was infused continuously to prevent variations in transcellular NaCl reabsorption when sodium reabsorption was altered by varying plasma PCO2 and glomerular filtration rate (GFR). At high plasma PCO2 (110 mmHg) sodium reabsorption varied in proportion to GRF between 50 and 125% of control GFR (glomerulotubular balance). By reducing PCO2 to 20 mmHg, sodium reabsorption was reduced by 50-60% at constant GFR. The Na/O2 ratio was not significantly different during the two procedures and averaged 48 +/- 2. The ratio between changes in NaHCO3 reabsorption and oxygen consumption averaged 17 +/- 1, which is not significantly different from the Na/O2 ratio of Na-K-ATPase-dependent sodium transport. We propose that NaHCO3 is admitted to the cell by Na+/H+ exchange and that sodium is actively transported by Na-K-ATPase across the peritubular cell membrane; NaHCO3 provides the osmotic force for paracellular reabsorption of water and NaCl (bicarbonate-dependent reabsorption) without additional energy requirement.

The control of sodium excretion

The kidneys of a normal man filter approximately 24,000 meq sodium/day, reabsorb about 23,900, and yet can make a 1--2 meq change in 24-h urinary sodium excretion. The control of urinary sodium excretion, therefore, depends, first, on ensuring that the bulk of the sodium is reabsorbed, a function which is carried out in the proximal tubule and ascending loop of Henle. Second, it depends on adjusting the reabsorption of the small quantity of sodium which is delivered into the collecting duct so that the amount excreted in the urine is that required to maintain sodium balance. The bulk reabsorptive mechanisms can be considered as buffers to prevent large fluctuations in the amount of sodium delivered to the collecting duct, thus facilitating the fine adjustments of reabsorption which are made at this site. In conditions other than extreme salt loading or deprivation, changes in sodium reabsorption in the proximal tubule and loop of Henle probably have little, if any, effect on urinary sodium excretion. Sodium reabsorption in the proximal tubule and the collecting duct appears to be influenced by unidentified circulating substances.

Studies on the pathophysiology of acute renal failure

Acute renal failure was induced in male rats by the subcutaneous injectioon of 4 mg HgC12 per kg body weight. Enzyme activities of the proximal tubule were studied histochemically at six time intervals from 15 min to 24 h. The enzyme studied were alkaline phosphatase, 5'-nucleotidase, acid phosphatase, alpha-glycerophosphate dehydrogenase (NAD-independent), malic dehydrogenase, succinic dehydrogenase, latic dehydrogenase, glucose-6-phosphate dehydrogenase and glucose-6-phosphatase. Decreases in activity were observed for alkaline phosphatase and 5'-nucleotidase after 15 min. Acid phosphatase was decreased after 30 min. These three enzymes returned to control levels after 3 h, but malic dehydrogenase and alpha-glycerophosphate dehydrogenase were decreased at this time interval. Succinic dehydrogenase was first decreased after 6 h. The earliest morphological changes detectable by light microscopy were observed in pars recta tubules in the medullary rays after 6 h, a time when all enzymes studied showed widespread decreased activity throughout the proximal tubule. After 24 h, the pars convoluta appeared morphologically normal but the pars recta was necrotic and exhibited calcification, whereas enzyme activity was decreased (absent in some cases) in both pars convoluta and pars recta. These results support the hypothesis that Hg++, when given in a sublethal dose, is associated with early histochemical changes in the brush border of the proximal tubule, which may be related to early changes in sodium reabsorption and to the subsequent development of acute renal failure. The observation that changes in plasma membrane-associated enzymes occur early and prior to alterations in enzymes of mitochondria and the endoplasmic reticulum suggests that Hg++ interacts initially with the plasma membrane.

Dopamine-induced dissociation between renal metabolic rate and sodium reabsorption.

The stimulatory effect of dopamine on renal energy metabolism and its relationship to changes in tubular sodium reabsorption and plasma concentration of free fatty acids (FFA) were examined in anesthetized dogs. Dopamine infused intravenously at 25 mug/kg body wt-min for 30-60 min increased renal oxygen consumption (Rvo2) by 28 +/- 3%; glomerular filtration rate rose from 37 +/- 3 to 40 +/- 2 ml/min without significant changes in sodium excretion. Plasma FFA increased about 6 times. Total-body metabolic rate increased to 152 +/- 7% and fell to 119 +/- 5% of control after normalizing plasma FFA by beta-pyridylcarbinol; Rvo2 remained unchanged. Cortical and outer medullary heat accumulation rated increased to 137 +/- 6 and 133 +/- 10% after 1 h and to 163 +/- 18 and 179 +/- 26% of control after 2 h of dopamine infusion without further changes in sodium reabsorption. Furosemide reduced cortical and outer medullary metabolic rates as much as in control experiments (14 +/- 8 and 69 +/- 7%, respectively). Hence, dopamine exerts a renal calorigenic effect which cannot be accounted for by increased sodium reabsorption or attributed to increased supply of FFA.

Independence of onset of compensatory kidney growth from changes in renal function.

Renal function was measure before and shortly after uninephrectomy in mice to evaluate if work expended in the reabsorption of glomerular filtrate plays a role in the initiation of compensatory growth. To exclude the possibility of small but undetectable increments in glomerular filtration rate and absolute sodium reabsorption these functions were experimentally reduced immediately after uninephrectomy and sham nephrectomy. The onset of growth was indicated by an increased rate of [14C]choline incorporation into phospholipid in renal cortical slices. [14C]choline incorporation increased significantly only after uninephrectomy and remained unchanged after sham operation regardless of the magnitude or direction of the concurrent change in sodium reabsorption. The rate of incorporation increased by 40 +/- 8% (P less than 0.005) in uninephrectomized animals whose sodium reabsorption was reduced by 34 +/- 6% (P less than 0.001) and rose 45 +/- 11% (P less than 0.005) when sodium reabsorption remained unchanged. These results indicate that compensatory kidney growth is not triggered by an increase in renal work expended in the reabsorption of glomerular filtrate; in fact, it can occur when reabsorptive work is substantially decreased.

Effect of extracellular volume expansion on renal cortical and medullary Na + -K + -ATPase.

The role of renal Na+−K+-ATPase in the acute changes in sodium reabsorption caused by isotonic volume expansion was evaluatedin vivo andin vitro in the rat and the dog. Duringin vivo volume expansion with isotonic saline in the rat, renal medullary Na+−K+-ATPase specific activity increased, while the simultaneously determined cortical Na+−K+-ATPase specific activity and kinetics remained unchanged. Furthermore, experimentsin vitro failed to demonstrate a circulating inhibitor of renal Na+−K+-ATPase both in plasma dialysates from volume-expanded rats and in plasma dialysates concentrated 20-fold by ultrafiltration from volume-expanded dogs. These results suggest that the decreased proximal tubular reabsorption of sodium during volume expansion is not mediated by inhibition of renal cortical Na+−K+-ATPase. The acute increment in medullary Na+−K+-ATPase observed could represent an adaptive response to increased sodium reabsorption by the loops of Henle, and raises the possibility that this enzyme may participate in relatively rapid adjustments in the transport of sodium by the renal tubule.

Effects of hematocrit on renal hemodynamics and sodium excretion in hydropenic and volume-expanded dogs.

The effects of hematocrit on renal hemodynamics and sodium excretion were studied in anesthetized dogs during both hydropenia and volume expansion. The hematocrit was decreased by isovolemic exchange with the animal's own previously harvested plasma and increased by isovolemic exchange with fresh, washed red blood cells. Renal perfusion pressure was maintained constant throughout the experiments by the adjustment of a suprarenal aortic clamp. During hydropenia, a decrease in hematocrit was associated with an increase in sodium and potassium excretion and solutefree water reabsorption. These changes were accompained by an increase in renal plasma flow and renal blood flow and a decrease in renal vascular resistance. Glomerular filtration rate was unchanged and filtration fraction was significantly decreased as hematocrit was lowered. Increasing hematocrit during hydropenia had the opposite effects on electrolyte excretion, solute-free water reabsorption, and renal hemodynamics. In another group of animals, hematocrit was lowered during volume expansion with either saline or plasma, then returned to the control level by isovolemic exchange with washed red blood cells. This increase in hematocrit during volume expansion had a similar effect on electrolyte excretion, solute-free water reabsorption, and renal hemodynamics as during hydropenia. These results therefore suggest that acute changes in hematocrit may significantly affect sodium excretion and renal hemodynamics during both hydropenia and volume expansion. The changes in solute-free water reabsorption and potassium excretion suggest that the alterations in hematocrit may affect primarily the reabsorption of sodium in the proximal tubule. The concommitant effects of hematocrit on renal vascular resistance and filtration fraction may mediate this change in sodium reabsorption by altering hydrostatic and oncotic pressures in the peritubular circulation.

Relationship between intrarenal hydrostatic pressure and hemodynamically induced changes in sodium excretion.

Deep intrarenal venous pressure was used as an index of renal capillary pressure to test the proposal that physically induced changes in sodium reabsorption may be mediated by changes in Starling forces across the capillary. Renal vasodilatation produced natriuresis associated with immediate increases in intrarenal venous pressure. Increased arterial pressure was accompanied by further natriuresis and initially increased intrarenal pressure in vasodilated kidneys. Plasma load was always accompanied by increased intrarenal venous pressure. Saline loading usually increased intrarenal venous pressure, and restoration of plasma protein concentration during saline loading reduced, but did not abolish, natriuresis. This continued natriuresis was associated with reduced renal vascular resistance and increased intrarenal venous pressure, demonstrating that continued natriuresis after restoring plasma oncotic pressure during saline loading could relate to increased capillary hydrostatic pressure. Intrarenal venous pressure did not relate to isolated changes in urine flow, arterial pressure, or renal blood flow. These observations support the hypothesis that changes in peritubular capillary hydrostatic pressure initiate changes in tubular sodium reabsorption as a result of changes in capillary uptake.

Sodium transport: inhibitory factor in sweat of patients with cystic fibrosis.

A factor inhibitory to sodium transport exists in the sweat of patients with cystic fibrosis of the pancreas. When the duct system of the rat parotid was perfused with sweat from patients, marked inhibition of sodium reabsorption was observed. Perfusion with sweat from normal subjects caused no change in sodium reabsorption. The factor thus demonstrated may be responsible for the increased sodium concentrations in the sweat of patients with cystic fibrosis.